In one aspect, the present invention relates to new pharmaceutical compositions containing 2,6-diisopropylphenol, known as propofol, and sulfite. In another aspect, the present invention relates to the use of these compositions to induce anesthesia in mammals, including sedation, and the induction and maintenance of general anesthesia. In yet another aspect, the present invention relates to the use of sulfite as a preservative for parenterally administered oil-in-water emulsions, in general. In still another aspect, the present invention relates to a process for the manufacture of oil-in-water emulsions containing sulfite as a preservative.
2,6-Diisopropylphenol, generically named propofol, is a well-known and widely-used, injectable anesthetic with hypnotic properties used both as a sedative, and to induce and maintain general anesthesia. It is sold as Diprivan (trademark Zeneca) for human use and Rapinovet (trademark Zeneca) for veterinary use. Propofol is administered directly into the bloodstream either by bolus injection or by infusion. Because the onset of anesthesia is largely controlled by a drug""s diffusion rate through the blood-brain barrier, propofol""s lipophilicity is key to its rapid activity. This lipophilicity, however, renders propofol relatively insoluble in water, hence it must be administered in conjunction with solubilizing agents, surfactants, or solvents; or as oil-in-water emulsions (Jones et al. (1998) U.S. Pat. No. 5,714,520). All references cited herein are incorporated by reference in their entirety.
As a parenterally administered agent, sterility of propofol formulations is essential. Commercial formulations are oil-in-water emulsions containing approximately 1%-2% propofol in 10% soybean oil. These formulations also typically contain a surfactant, 1.2% egg phosphatide for example, 2.25% glycerol to make the formulation isotonic, sodium hydroxide to adjust the pH to physiological pH, and 0.005% EDTA equivalent (as edetate) to retard microbiological growth (all weights approximate) (Id.). Edetate containing formulations are not antimicrobially preserved by USP standards; however, microbial growth is retarded (Id.).
Non-preserved, propofol oil-in-water emulsion formulations have significant drawbacks arising from the fact that these formulations support microbial growth: strict aseptic handling technique is required; maximum utility time is 12 h maximum after vial entry. Handling recommendations include immediate administration after vial entry, and disposal of infusion assemblies and of unused material after 12 h. Nevertheless, reports of nosocomial infections resulting from adventitious contamination are not uncommon (Bennett et al. (1995) N. Engl. J. Med. 333:147-154). Improper handling techniques include delayed administration after transfer from vial to syringe, use of 50- and 100-mL products as multi-use, for multiple patients, and use of 50 and 100 mL products for an extended time period.
An application for which preserved propofol formulations are particularly advantageous is their use as a long-term sedative by continuous infusion. The risk of microbial contamination of non-preserved propofol in infusion devices increases both with residency-time in the infusion device, and with increased manipulation of the device. The utility time of formulations containing EDTA salts (edetates) is at least 24 h compared to 6 to 12 h for non-preserved formulations (Jones et al.). A longer lasting formulation means that fewer manipulations are required. The consequent reduced manipulation accrues a number of important benefits: reduced probability of microbial contamination, reduced probability of operator error, reduced drug waste, and reduced labor intensivenessxe2x80x94all of which combine to increase safety and reduce costs.
An extensive and vigorous evaluation of known antimicrobial agents for parenteral products led to the unexpected discovery that sulfite can be included in an oil-in-water emulsion of propofol in a non-toxic amount which is soluble in the aqueous phase and does not partition into the organic phase, and which retards or suppresses the of growth of likely microbial contaminants, without destabilizing the emulsion and without adversely reacting with other formulation components. These results are especially surprising in light of published data indicating that sodium metabisulfite is completely ineffectual for this particular application (1% Diprivan (Zeneca) 0.1% Na2S2O5) (Jones et al.)
Sodium metabisulfite is a salt of a sulfurous acid (formally, metasulfurous acid). The present invention includes all pharmaceutically acceptable derivatives of sulfurous acid (orthosulfurous acid) and metasulfurous acid approved by the FDA for human use (sulfites) and any combinations thereof. These compounds include, but are not limited to, sodium sulfite, sodium bisulfite, potassium sulfite, potassium bisulfite, sodium metabisulfite, and potassium metabisulfite.
Accordingly, the present invention provides a sterile composition for parenteral administration comprising an oil-in-water emulsion in which propofol is dissolved in a water-immiscible solvent that is emulsified with water wherein said emulsion is stabilized by means of a surfactant. The composition further comprises an amount of a sulfite sufficient to exhibit antimicrobial activity against microorganisms most likely to contaminate the propofol preparation.
The present invention also includes the use of sulfites as preservatives for any sterile, parenterally administered oil-in-water emulsion. In addition to propofol compositions, such formulations include total-parenteral-nutrition formulations, or oil-in-water vehicles for other pharmaceutical or therapeutic agents.
Additionally, the present invention includes a process for the manufacture of sterile, propofol oil-in-water emulsions for parenteral administration comprising propofol dissolved into a water-immiscible liquid emulsified with water, wherein said emulsion is stabilized by means of a surfactant and further comprising effective amounts of sulfite as a preservative. Timing of the addition of the sulfite and control of the process temperature are both critical to the maintenance of antimicrobial activity in the composition. This aspect of the invention may be advantageously applied to other drugs formulated as an oil-in water emulsion.
In accordance with the present invention and as used herein, the following terms are defined to have the following meanings, unless explicitly stated otherwise:
The term xe2x80x9cedetatexe2x80x9d refers to an anion derived from deprotonation of EDTA. EDTA is a tetrabasic acid, thus an edetate may be mono-, di-, tri- or tetraanionic. The term xe2x80x9cedetatexe2x80x9d may also refer to a salt of an edetate anion.
The term xe2x80x9coil-in-water emulsionxe2x80x9d refers to a distinct two phase system that is in equilibrium and in effect, as a whole, is kinetically stable and thermodynamically unstable.
The term xe2x80x9cpreservativexe2x80x9d refers to an agent or agents that suppress or prevent microbiological growth at 24 h by no more than 10-fold compared to time-zero.
The term xe2x80x9csulfitexe2x80x9d refers to all pharmaceutically acceptable derivatives of sulfurous acid (orthosulfurous acid) and metasulfurous acid approved by the FDA now or in the future for human use. These compounds include sodium sulfite, sodium bisulfite, potassium sulfite, potassium bisulfite, sodium metabisulfite, and potassium metabisulfite.